Project Abstract
Dementias such as Alzheimer’s disease are one of the leading causes of death worldwide, and despite an increasing incidence, there are currently no effective treatments against these debilitating diseases. Development of therapies has been hampered by a lack of mechanistic understanding of events that underlie the disease. Two hallmarks of the disease are abnormal aggregation of the protein amyloid-beta and inflammation. In this project we aim to link these two key features, and contribute to our understanding of pathological mechanisms in Alzheimer’s disease by characterising a critical protein interaction, between amyloid-beta and the immune receptor protein TREM2, in molecular detail. We will perform a thorough biophysical and structural characterisation of this important interaction, identifying the specific aggregation states of amyloid-beta that directly interact with TREM2. We will determine molecular consequences of the interaction, using structural methods to model the complex, and determine how disease-linked mutations affect this critical interaction. This work will establish crucial information on the molecular pathology of Alzheimer’s disease, providing targets for the development of therapies to block harmful interactions to treat Alzheimer’s disease.
